Management of transient bone osteoporosis: a systematic review

Abstract Introduction Transient bone osteoporosis (TBO) is characterized by persistent pain, loss of function, no history of trauma and magnetic resonance image (MRI) findings of bone marrow edema. Source of data PubMed, Google scholar, EMABSE and Web of Science were accessed in February 2023. No time constrains were used for the search. Areas of agreement TBO is rare and misunderstood, typically affecting women during the third trimester of pregnancy or middle-aged men, leading to functional disability for 4–8 weeks followed by self-resolution of the symptoms. Areas of controversy Given the limited evidence in the current literature, consensus on optimal management is lacking. Growing points This systematic review investigates current management of TBO. Areas timely for developing research A conservative approach leads to the resolution of symptoms and MRI findings at midterm follow-up. Administration of bisphosphonates might alleviate pain and accelerate both clinical and imaging recovery.


Introduction
Transient bone osteoporosis (TBO) is a rare, misdiagnosed, self-limiting condition of unclear etiology.TBO is characterized by pain, 1 loss of function, absence of previous trauma, 2 osteopenia on plain radiography and bone marrow edema at magnetic resonance imaging (MRI). 3TBO typically affects middle-aged men 4 or, less commonly, women during the third trimester of pregnancy and the immediate post-partum period. 5 ,6TBO usually presents with sudden-onset pain in weight-bearing areas, especially in the lower limb, often radiating distally. 7,8In most patients, TBO leads to functional disability within 4-8 weeks, followed by a gradual disappearance of the symptoms in the following 6-12 months. 9 ,10he clinical examination might demonstrate limited effusion.Imaging, including plain radiographs, bone scans and MRI, is used for the diagnosis.MRI is fundamental for the diagnosis, evidencing nonspecific and localized bone marrow edema hyperintense in T2 sequences. 6,7,11,12TBO should be differentiated from bone osteonecrosis and metastases. 13,14Other less common conditions to consider for the differential diagnosis are regional migratory osteoporosis, reflex sympathetic dystrophy, arthritis of various etiologies such as septic arthritis, osteomyelitis and insufficiency fracture. 15evertheless, it remains a diagnosis of exclusion, usually delayed, partly from the lack of awareness. 16espite a benign prognosis, the long clinical course causes prolonged disability.Given the limited evidence in the current literature, consensus on optimal management is lacking.In most cases, conservative management allows the resolution of symptoms within 6-12 months. 17The main conservative approaches include restricted weightbearing, anti-resorptive medications and analgesics. 6This systematic review investigates current management of TBO.

Eligibility criteria
All the clinical studies, which investigated modalities for the management of TBO, were accessed.According to the author's language capabilities, articles in English, German, Italian, French and Spanish were eligible.Levels I to IV of evidence studies, according to Oxford Centre of Evidence-Based Medicine, 18 were considered.Reviews, opinions, letters, editorials, animals, in vitro, biomechanics, computational and cadaveric investigations were not considered.

Search strategy
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the 2020 PRISMA statement. 19The following PICO algorithm was established for the databases search:

Selection and data collection
Two authors (F.M. & G.V.) independently conducted the databases search.All the resulting titles were screened by hand and the abstract of the articles, which matched the topic was read.The full texts of the abstracts of interest were accessed.The bibliographies of the full-text articles were also screened by hand.Any disagreements were discussed and settled by a third senior author (N.M.).

Data items
Two authors (F.M. & G.V.) independently performed data extraction.The following data were extracted: author and year, name of the journal and study design, length of the follow-up, number of included patients, type and number of joints, mean age and body mass index (BMI) of the included patients, number of women, type of treatment and main findings.

Study risk of bias assessment
The methodological index for non-randomized studies (MINORS) was performed to evaluate the quality of the included article. 20The MINORS involves eight items for non-comparative studies and 12 items for comparative studies.The MINORS optimal global score is 16 points for the non-comparative studies and 24 points for the comparative studies.

Synthesis methods
For descriptive statistics, the IBM software version 25 was used.The arithmetic mean and standard deviation were used for continuous variables.

Study selection
The literature search resulted in 416 clinical studies.Duplicate records (N = 107) were excluded.A further 285 articles were excluded with reason: not matching the topic (N = 181), inappropriate study design (N = 98), language limitation (N = 2) and fulltext not available (N = 1).A further three articles did not report quantitative data under the outcome of interest, and were thus excluded.This left 21 articles for inclusion.The flow chart of the literature search is shown in Figure 1.

Methodological quality assessment
Based on the MINORS scale, the 20 non-comparative studies had a medium score of 6.6 and the only comparative study scored 20 points.The MINORS attested to the present study a low quality of the methodological assessment (Table 1).

Synthesis of results
Data from 65 patients (74 treated joints) were collected.About, 23% (15 of 65) were women.The mean length of the follow-up was 14.4 months.The mean age of the patients was 38.1 ± 10.4 years, and the mean BMI was 28.8 kg/m 2 .The conservative management of TBO proved to be effective at middle and long-term follow-up, evaluating the resolution of symptoms and MRI findings.Treatment with bisphosphonates seems to alleviate pain and accelerate both clinical and imaging recovery.Generalities, patient characteristics and main results of the included studies are shown in Table 2.

Discussion
According to the main findings of the present study, conservative management leads to the resolution of symptoms and MRI findings at midterm follow-up.Administration of bisphosphonates might alleviate pain and accelerate clinical recovery and imaging appearance.
23][24][25][26]39 Vaishya et al. 27 conducted a study analyzing 12 hips in 14 patients with hip TBO treated conservatively.All the patients returned to work with a complete resolution of symptoms at 17.1 weeks. 27At 1.3-year followup, no recurrence was observed in any patient. 27aishareh et al. performed an observational study on 15 patients with symptomatic hip TBO. 28The mean age of the patients was 41 years. 28Ten of 15 patients underwent core decompression and 5 patients were treated conservatively. 28The time needed for full recovery was 5.8 weeks for those who underwent drilling and 48.3 weeks for the three patients treated conservatively. 28Two patients who underwent conservative management did not achieve full recovery at the time of follow-up. 28The author hypothesized that hip core decompression could be considered as a treatment modality to achieve faster recovery in patients with hip TBO. 28reatment with bisphosphonates has shown promising results, shortening the duration of symptoms. 8 ,9 ,29Agarwala et al. 30  Calcium and vitamin D were also supplemented. 3After 3 months, the patient reported a complete resolution of symptoms and disability. 3Three years later, following onset of TBO contralaterally, the same treatment was administered, obtaining the same results at 2 months follow-up. 3Furthermore, they presented the case of a 64-year-old with a two-week history of progressively increasing left knee pain.A high-resolution MRI of his left distal femur revealed deterioration in bone microarchitecture (manifested by trabecular loss and disruption). 3The regional bone mineral density of his left lateral femoral condyle was 0.96 g/cm 2.3 The patient continued with routine calcium and vitamin D supplementation. 3The patient reported spontaneous resolution of his knee pain over months. 3A further regional knee bone density of the left lateral femoral condyle showed marked improvement of 1.63 g/cm 2 at one year of follow-up. 3Pande et al. 31 reported a 43-year-old male patient with hip TBO managed by weightbearing restriction, physiotherapy, administration of alendronate 10 mg daily, and calcium and vitamin D supplementations.At seven weeks, the patient evidenced a complete remission of symptoms with a complete recovery of the full range of motion. 31t five months follow-up, no evidence of TBO was observed at MRI and the administration of alendronate was discontinued. 31At seven months   follow-up, the patient resumed normal activities.Paoletta et al. 32 described a 46-year-old man with a diagnosis of hip TBO treated with intramuscular clodronate 200 mg for a month and weight-bearing restriction.Significant pain relief, improved motion, and a significant reduction of bone edema at MRI scans was observed at 2 months follow-up. 32Seok et al. 9 presented the case of a 46-year-old male with a diagnosis of hip TBO, treated with a single dose of intravenous zoledronate 5 mg, weight-bearing restriction and hot packs. 9Despite a slight pain in the inguinal area, no pain was observed during weight bearing at the two-week follow-up.Additional 2 weeks of limited weight bearing were recommended. 9At four weeks follow-up, the pain in the inguinal area disappeared.At six months follow-up, no evidence of TBO was observed at MRI. 9 TBO and especially transient osteoporosis of the hip frequently occurs in pregnant women in the third trimester or in the immediate postpartum period. 1 ,7,16,26,33,34,38 Pregnancy limits the choices of pharmacotherapy.Brodell et al. 35 suggested that the benefit of radiographic imaging may outweigh the potential risks in the third trimester of pregnancy.Furthermore, gold standard diagnostic imaging is via MRI, which should be considered a safe modality in the third trimester. 36Cesarean section is preferable to vaginal delivery to avoid the risk of trauma to the weak head of the femur in cases of TBO of the hip. 1 The present study has several limitations.The overall quality of the evidence was low.Most of the available data come from case reports and retrospective studies.In this respect, results are not fully generalizable.Given the rarity of TBO, highquality studies on a larger scale are arduous.Between studies, patient characteristics were heterogeneous.Given these limitations, the results of the present study must be considered with caution.

Conclusion
A conservative approach leads to the resolution of symptoms and MRI findings of TBO at midterm follow-up.Administration of bisphosphonates seems to alleviate pain and accelerate both clinical and imaging recovery.

Fig. 1
Fig. 1 Flow chart of the literature search.

Table 2
Generalities, patient characteristics and main results of the included studies